This program project grant will determine the imaging, emotional, social-cognitive, language, genetic and diagnostic features of frontotemporal lobar degeneration (FTLD) and related disorders including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) in contrast to Alzheimer's disease (AD) and healthy aging. In project 2 we will explore the imaging features of the three major FTLD syndromes and a new cohort of patients with ALS using a 4.0 Tesla magnet. This project will use new imaging techniques including tensor-based morphometry, perfusion and diffusion tensor imaging. In project three we will use methods derived from basic emotion research to evaluate emotional functioning (reactivity, regulation, knowledge) in all three FTLD subtypes compared to AD. Dyads interaction between patients and caregivers, low-level emotion processing and higher order reactions to these basic emotional stimulations will be determined. Project 4 will use all of the information captured through the clinical core, genetics core as well as new amyloid imaging and proteomics parameters to explore better separation of FTLD subtypes from each other and from AD, early diagnosis and better prediction of patients with FTLD-associated tau pathology from those with FTLD-ubiquitin pathology. A new project 5 explores brain-behavior relationships in FTLD using novel and innovative cognitive and social probes. Using 4.0 Tesla scans from project 2 the relationship between changes in the dorsal frontal regions and specific aspects of cognitive control of motor responses and regulation of emotion, the relationship between changes in the ventral and medial prefrontal regions and activation of the emotional systems for monitoring of behavior and the relationship between the anterior temporal lobe and comprehension of verbal and non-verbal stimuli will be explored. Project 1 which was focused upon finding novel genes associated with FTLD is replaced by a Genetics Core that will not only perform routine studies of apolipoprotein E, tau, and presenilin 1, but will also explore mRNA expression of tau-related and frontal lobe related genes. Through the Clincial Core novel assessment of 107 AD, 131 FTD, 67 SD, 56 PNFA, 43 CBD, 30 PSP, 59 ALS, and 89 controls will be completed by year 10. Neuropathology will be completed in 37 AD, 64 FTD, 25 SD, 23 PNFA, 23 CBD, 23 PSP and 27 ALS patients. This PPG represents one of the largest efforts to understand the clinical features of FTLD ever performed.